IMPORTANCE Vitiligo is an autoimmune skin disorder that reacts against melanocytes. The association of vitiligo with tumor response in patients with melanoma who undergo immunotherapy has been reported but is still controversial. OBJECTIVE To prospectively evaluate the appearance of vitiligo in patients receiving pembrolizumab, a monoclonal antibody directed against the programmed death cell receptor. DESIGN, SETTING, AND PARTICIPANTS This prospective observational study was conducted from January 1, 2012, through September 24, 2013, in a single tertiary care hospital with a unit dedicated to patients with melanoma. Sixty-seven patients with metastatic melanoma who received pembrolizumab treatment in the context of a phase 1 study were included and screened for the emergence of vitiligo. Data were collected from January 1, 2012, to February 28, 2014, and analyzed from February through December 2014. MAIN OUTCOMES AND MEASURES Objective tumor response with regard to the occurrence of vitiligo in patients receiving pembrolizumab therapy. Correlation between vitiligo occurrence and overall survival was also estimated using the Kaplan-Meier product-limit method and compared with a log-rank test. To prevent guarantee-or lead-time bias, a landmark analysis approach after 12, 16, and 20 weeks of treatment was retained. RESULTS Of the 67 patients included in the study, 17 (25%) developed vitiligo during pembrolizumab treatment and 50 (75%) did not. An objective (complete or partial) response to treatment was associated with a higher occurrence of vitiligo (12 of 17 [71%] vs 14 of 50 [28%]; P = .002). The time to onset of vitiligo ranged from 52 to 453 (median, 126) days from the start of treatment. Of the 17 patients with vitiligo, 3 (18%) had a complete response, 9 (53%) had a partial response, 3 (18%) had stable disease, and 2 (12%) had progressive disease at the final follow-up. All the patients treated with pembrolizumab who developed vitiligo were alive at the time of analysis, with a median follow-up of 441 days. CONCLUSIONS AND RELEVANCE Vitiligo, a clinically visible immune-related adverse event could be associated with clinical benefit in the context of pembrolizumab treatment.

Ipilimumab toxic effect is manageable in real life. Biological data such as lymphocyte and eosinophil counts at the time of the second ipilimumab infusion appear to be early markers associated with better OS.

A numerical model for describing bipolar charge transport and storage in polyethylene has been developed recently. The present paper proposes a comparison of the model outputs with experimental data in three different direct current (DC) voltage application protocols (step field increase and polarization/depolarization schemes). Three kinds of measurement have been realized for the three different protocols: space charge distribution using the pulsed electro-acoustic method, external current and electroluminescence. Simulation under AC stress has also been attempted on the basis of the model parameters that were derived from the DC case. Model limitations and possible improvements are discussed.

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We present a conduction model aimed at describing bipolar transport and space charge phenomena in low density polyethylene under dc stress. In the first part we recall the basic requirements for the description of charge transport and charge storage in disordered media with emphasis on the case of polyethylene. A quick review of available conduction models is presented and our approach is compared with these models. Then, the bases of the model are described and related assumptions are discussed. Finally, results on external current, trapped and free space charge distributions, field distribution and recombination rate are presented and discussed, considering a constant dc voltage, a step-increase of the voltage, and a polarization–depolarization protocol for the applied voltage. It is shown that the model is able to describe the general features reported for external current, electroluminescence and charge distribution in polyethylene.

We introduce and develop two bipolar transport models which are based on appreciably different physical assumptions regarding the distribution function in the energy levels of trap states. In the first model, conduction is described by an effective mobility of the carriers and the accumulation of stored space charge is taken into account through a single trapping level. In the second model the hypothesis of an exponential distribution function of trap depth is made, with conduction taking place via a hopping process from site to site. The results of simulations of the two models are compared with experimental data for the external current and the space-time evolution of the electrical space charge distribution. The two descriptions are evaluated in a critical way, and the prospects for these models to adequately describe real systems are given.

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Highlights d Melanoma persister cells switch from glycolysis to mitochondrial respiration d Fatty acid oxidation (FAO) signature is upregulated in melanoma persister cells d Peroxisomal FAO is mediated by PPARa-ACOX1 axis in persister cells d Peroxisomal FAO inhibition delays the emergence of resistance to targeted therapy